Bampi Giovana B, Ramalho Anabela S, Santos Leonardo A, Wagner Johannes, Dupont Lieven, Cuppens Harry, De Boeck Kris, Ignatova Zoya
Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, 20146 Hamburg, Germany.
CF Organoids Research Lab, Woman and Child Unit, Department of Development and Regeneration, University of Leuven, 3000 Leuven, Belgium.
Life (Basel). 2020 Dec 27;11(1):14. doi: 10.3390/life11010014.
Synonymous single nucleotide polymorphisms (sSNPs), which change a nucleotide, but not the encoded amino acid, are perceived as neutral to protein function and thus, classified as benign. We report a patient who was diagnosed with cystic fibrosis (CF) at an advanced age and presented very mild CF symptoms. The sequencing of the whole cystic fibrosis transmembrane conductance regulator () gene locus revealed that the patient lacks known CF-causing mutations. We found a homozygous sSNP (c.1584G>A) at the end of exon 11 in the gene. Using sensitive molecular methods, we report that the c.1584G>A sSNP causes cognate exon skipping and retention of a sequence from the downstream intron, both of which, however, occur at a relatively low frequency. In addition, we found two other sSNPs (c.2562T>G (p.Thr854=) and c.4389G>A (p.Gln1463=)), for which the patient is also homozygous. These two sSNPs stabilize the CFTR protein expression, compensating, at least in part, for the c.1584G>A-triggered inefficient splicing. Our data highlight the importance of considering sSNPs when assessing the effect(s) of complex CFTR alleles. sSNPs may epistatically modulate mRNA and protein expression levels and consequently influence disease phenotype and progression.
同义单核苷酸多态性（sSNPs），即改变一个核苷酸但不改变编码氨基酸的多态性，被认为对蛋白质功能呈中性，因此被归类为良性。我们报告了一名在高龄时被诊断为囊性纤维化（CF）且表现出非常轻微CF症状的患者。对整个囊性纤维化跨膜传导调节因子（CFTR）基因位点进行测序后发现，该患者不存在已知的导致CF的突变。我们在CFTR基因第11外显子末端发现了一个纯合的sSNP（c.1584G>A）。通过使用灵敏的分子方法，我们报告c.1584G>A sSNP会导致同源外显子跳跃以及保留来自下游内含子的一个序列，然而这两种情况都以相对较低的频率发生。此外，我们还发现了另外两个sSNP（c.2562T>G（p.Thr854=）和c.4389G>A（p.Gln1463=）），该患者同样为这两个sSNP的纯合子。这两个sSNP稳定了CFTR蛋白的表达，至少部分补偿了由c.1584G>A引发的低效剪接。我们的数据突出了在评估复杂CFTR等位基因的效应时考虑sSNP的重要性。sSNP可能会上位性地调节mRNA和蛋白质表达水平，从而影响疾病表型和进展。
